A genetic variation located in the promoter region of the UPAR (CD87) gene is associated with the vascular complications of systemic sclerosis

Objective. The uPAR gene encodes a pleiotropic receptor involved in fibrosis, immunity,
angiogenesis and vascular remodeling. Previous studies have implicated uPAR in systemic sclerosis
(SSc) vasculopathy and impaired angiogenesis. We investigated whether uPAR gene promoter
polymorphisms may be associated with SSc phenotypes in the European Caucasian population.
Methods. A total population of 1,339 individuals was studied. The Italian discovery cohort
comprised 388 SSc patients and 391 healthy controls. The French replication cohort consisted of 344
SSc patients and 216 healthy controls. The uPAR rs344781 and rs4251805 single-nucleotide
polymorphisms were genotyped by PCR-RFLP assay.
Results. In the Italian cohort, the rs344781 G allele was associated with SSc-related digital
ulceration (DU) (OR 1.39), pulmonary arterial hypertension (PAH) (OR 1.81), anticentromere
antibody (ACA)-positivity (OR 1.45) and limited cutaneous SSc (lcSSc) (OR 1.37). The rs344781
GG genotype was associated with SSc-PAH (OR 3.79), ACA-positive SSc (OR 2.17) and lcSSc (OR
1.96). Allelic and genotypic associations with SSc-DU and ACA-positive SSc were replicated in the
French sample. Combined analyses showed an association of the rs344781 G allele and GG
genotype with SSc-DU (allele OR 1.41; genotype OR 2.15), SSc-PAH (allele OR 1.65; genotype OR
3.16), ACA-positive SSc (allele OR 1.47; genotype OR 2.40) and lcSSc (allele OR 1.34; genotype
OR 1.77). In a multivariate logistic regression analysis model including the above associated
phenotypes of SSc patients, the rs344781 GG genotype remained an independent risk factor for SSc-
DU (OR 1.96) and SSc-PAH (OR 2.68).
Conclusion. The uPAR rs344781 gene variant is associated with SSc vascular phenotype.